JP5784620B2 - カゼインキナーゼ阻害剤としてのイミダゾール誘導体 - Google Patents

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Publication number

JP5784620B2

JP5784620B2 JP2012535977A JP2012535977A JP5784620B2 JP 5784620 B2 JP5784620 B2 JP 5784620B2 JP 2012535977 A JP2012535977 A JP 2012535977A JP 2012535977 A JP2012535977 A JP 2012535977A JP 5784620 B2 JP5784620 B2 JP 5784620B2

Authority

JP

Japan

Prior art keywords

imidazol

fluorophenyl

pyrimidin

alkyl

amine

Prior art date

2009-10-28

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 108010031425 Casein Kinases Proteins 0.000 title description 5
• 102000005403 Casein Kinases Human genes 0.000 title description 5
• 150000002460 imidazoles Chemical class 0.000 title description 3
• 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 title 1
• 229940043355 kinase inhibitor Drugs 0.000 title 1
• 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
• -1 isoxazol-3-ylmethyl Chemical group 0.000 claims description 162
• 150000001875 compounds Chemical class 0.000 claims description 132
• 125000001424 substituent group Chemical group 0.000 claims description 82
• 125000000217 alkyl group Chemical group 0.000 claims description 78
• 239000000203 mixture Substances 0.000 claims description 68
• 239000001257 hydrogen Substances 0.000 claims description 53
• 229910052739 hydrogen Inorganic materials 0.000 claims description 53
• 150000003839 salts Chemical class 0.000 claims description 53
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 40
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 39
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 37
• 229910052799 carbon Inorganic materials 0.000 claims description 34
• 150000002367 halogens Chemical class 0.000 claims description 34
• 229910052736 halogen Inorganic materials 0.000 claims description 33
• 125000005842 heteroatom Chemical group 0.000 claims description 29
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 28
• 229910052757 nitrogen Inorganic materials 0.000 claims description 26
• 125000001072 heteroaryl group Chemical group 0.000 claims description 24
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
• 208000035475 disorder Diseases 0.000 claims description 20
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 16
• 229910052731 fluorine Inorganic materials 0.000 claims description 13
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
• 239000011737 fluorine Substances 0.000 claims description 11
• 101150047910 CSNK1D gene Proteins 0.000 claims description 10
• 208000020925 Bipolar disease Diseases 0.000 claims description 8
• 208000012902 Nervous system disease Diseases 0.000 claims description 8
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
• 230000000694 effects Effects 0.000 claims description 8
• 239000001301 oxygen Substances 0.000 claims description 8
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 7
• QLMXTWLZXLSYPY-UHFFFAOYSA-N 2-[[4-(4-phenyl-5-pyrimidin-4-ylimidazol-1-yl)piperidin-1-yl]methyl]pyrimidine Chemical compound N=1C=CC=NC=1CN(CC1)CCC1N1C=NC(C=2C=CC=CC=2)=C1C1=CC=NC=N1 QLMXTWLZXLSYPY-UHFFFAOYSA-N 0.000 claims description 7
• 208000019022 Mood disease Diseases 0.000 claims description 7
• 208000025966 Neurological disease Diseases 0.000 claims description 7
• 230000000926 neurological effect Effects 0.000 claims description 7
• 208000020016 psychiatric disease Diseases 0.000 claims description 7
• SMYILHSDBTWVCE-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-3-[1-(1,2-oxazol-3-ylmethyl)pyrrolidin-3-yl]imidazol-4-yl]pyrimidin-2-amine Chemical compound NC1=NC=CC(C=2N(C=NC=2C=2C=CC(F)=CC=2)C2CN(CC3=NOC=C3)CC2)=N1 SMYILHSDBTWVCE-UHFFFAOYSA-N 0.000 claims description 6
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 6
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
• 125000003545 alkoxy group Chemical group 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
• YLKRIZZCCGCJKZ-UHFFFAOYSA-N n-methyl-4-[5-phenyl-3-[1-(pyrimidin-2-ylmethyl)piperidin-4-yl]imidazol-4-yl]pyrimidin-2-amine Chemical compound CNC1=NC=CC(C=2N(C=NC=2C=2C=CC=CC=2)C2CCN(CC=3N=CC=CN=3)CC2)=N1 YLKRIZZCCGCJKZ-UHFFFAOYSA-N 0.000 claims description 6
• 208000019116 sleep disease Diseases 0.000 claims description 6
• 229910052717 sulfur Inorganic materials 0.000 claims description 6
• 239000011593 sulfur Substances 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 5
• XPWHRQHBPRSUAW-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-3-[1-(1,2-oxazol-3-ylmethyl)piperidin-4-yl]imidazol-4-yl]pyrimidin-2-amine Chemical compound NC1=NC=CC(C=2N(C=NC=2C=2C=CC(F)=CC=2)C2CCN(CC3=NOC=C3)CC2)=N1 XPWHRQHBPRSUAW-UHFFFAOYSA-N 0.000 claims description 4
• YOWNAAWVSZSZSY-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-3-[1-(pyrimidin-2-ylmethyl)piperidin-4-yl]imidazol-4-yl]pyrimidin-2-amine Chemical compound NC1=NC=CC(C=2N(C=NC=2C=2C=CC(F)=CC=2)C2CCN(CC=3N=CC=CN=3)CC2)=N1 YOWNAAWVSZSZSY-UHFFFAOYSA-N 0.000 claims description 4
• 230000027288 circadian rhythm Effects 0.000 claims description 4
• 201000010099 disease Diseases 0.000 claims description 3
• 230000002401 inhibitory effect Effects 0.000 claims description 3
• 230000005764 inhibitory process Effects 0.000 claims description 3
• 208000020685 sleep-wake disease Diseases 0.000 claims description 3
• 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 2
• ZJCNTDISYRIDDQ-UHFFFAOYSA-N 4-[3-[1-(1,2-oxazol-3-ylmethyl)piperidin-4-yl]-5-phenylimidazol-4-yl]pyrimidin-2-amine Chemical compound NC1=NC=CC(C=2N(C=NC=2C=2C=CC=CC=2)C2CCN(CC3=NOC=C3)CC2)=N1 ZJCNTDISYRIDDQ-UHFFFAOYSA-N 0.000 claims description 2
• RXNQNOUVAKIMHA-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-3-[1-(1,2-oxazol-3-ylmethyl)piperidin-4-yl]imidazol-4-yl]-n-methylpyrimidin-2-amine Chemical compound CNC1=NC=CC(C=2N(C=NC=2C=2C=CC(F)=CC=2)C2CCN(CC3=NOC=C3)CC2)=N1 RXNQNOUVAKIMHA-UHFFFAOYSA-N 0.000 claims description 2
• 230000002035 prolonged effect Effects 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 4
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 114
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
• 238000000034 method Methods 0.000 description 52
• 239000007787 solid Substances 0.000 description 51
• 239000000047 product Substances 0.000 description 50
• 239000000243 solution Substances 0.000 description 49
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
• 238000005481 NMR spectroscopy Methods 0.000 description 41
• 238000006243 chemical reaction Methods 0.000 description 39
• 125000004435 hydrogen atom Chemical class [H]* 0.000 description 29
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
• RGKNHYFXCGWJJS-UHFFFAOYSA-N 3-[[3-[4-(4-fluorophenyl)-5-pyrimidin-4-ylimidazol-1-yl]pyrrolidin-1-yl]methyl]-1,2-oxazole Chemical compound C1=CC(F)=CC=C1C1=C(C=2N=CN=CC=2)N(C2CN(CC3=NOC=C3)CC2)C=N1 RGKNHYFXCGWJJS-UHFFFAOYSA-N 0.000 description 26
• 206010028980 Neoplasm Diseases 0.000 description 25
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
• 125000003118 aryl group Chemical group 0.000 description 22
• 150000001721 carbon Chemical group 0.000 description 22
• 239000012044 organic layer Substances 0.000 description 22
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 239000012071 phase Substances 0.000 description 20
• 239000002904 solvent Substances 0.000 description 20
• 238000003786 synthesis reaction Methods 0.000 description 19
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• 125000004432 carbon atom Chemical group C* 0.000 description 18
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 18
• 239000003480 eluent Substances 0.000 description 17
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• 241000124008 Mammalia Species 0.000 description 15
• 230000015572 biosynthetic process Effects 0.000 description 15
• 239000003921 oil Substances 0.000 description 15
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 14
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 13
• 125000000753 cycloalkyl group Chemical group 0.000 description 13
• 229920006395 saturated elastomer Polymers 0.000 description 13
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
• 150000001299 aldehydes Chemical class 0.000 description 12
• 201000011510 cancer Diseases 0.000 description 12
• 239000010410 layer Substances 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• 238000010898 silica gel chromatography Methods 0.000 description 12
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 11
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
• 235000019341 magnesium sulphate Nutrition 0.000 description 11
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
• 208000009956 adenocarcinoma Diseases 0.000 description 10
• 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 10
• 208000010877 cognitive disease Diseases 0.000 description 10
• 239000003814 drug Substances 0.000 description 10
• 230000002829 reductive effect Effects 0.000 description 10
• 238000010992 reflux Methods 0.000 description 10
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 10
• 239000002253 acid Substances 0.000 description 9
• 239000003153 chemical reaction reagent Substances 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• 125000000623 heterocyclic group Chemical group 0.000 description 9
• 238000000746 purification Methods 0.000 description 9
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 9
• 125000006413 ring segment Chemical group 0.000 description 9
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
• DEBZZOLMKVPGDM-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-3-piperidin-4-ylimidazol-4-yl]pyrimidine Chemical compound C1=CC(F)=CC=C1C1=C(C=2N=CN=CC=2)N(C2CCNCC2)C=N1 DEBZZOLMKVPGDM-UHFFFAOYSA-N 0.000 description 8
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
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• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 8
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• 238000009472 formulation Methods 0.000 description 8
• 239000003112 inhibitor Substances 0.000 description 8
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• BHXCBVGMACZSEA-UHFFFAOYSA-N Cl.FC1=CC=C(C=C1)C=1N=CN(C1C1=NC=NC=C1)C1CCN(CC1)CC1=NOC=C1 Chemical compound Cl.FC1=CC=C(C=C1)C=1N=CN(C1C1=NC=NC=C1)C1CCN(CC1)CC1=NOC=C1 BHXCBVGMACZSEA-UHFFFAOYSA-N 0.000 description 7
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• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
• 239000002246 antineoplastic agent Substances 0.000 description 7
• 239000007864 aqueous solution Substances 0.000 description 7
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• KQARACZYDPHSII-UHFFFAOYSA-N n-methyl-4-(5-phenyl-3-piperidin-4-ylimidazol-4-yl)pyrimidin-2-amine Chemical compound CNC1=NC=CC(C=2N(C=NC=2C=2C=CC=CC=2)C2CCNCC2)=N1 KQARACZYDPHSII-UHFFFAOYSA-N 0.000 description 7
• 229910052938 sodium sulfate Inorganic materials 0.000 description 7
• 235000011152 sodium sulphate Nutrition 0.000 description 7
• RSVKJKGWCXEMRK-UHFFFAOYSA-N tert-butyl 3-[5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)imidazol-1-yl]azetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1N1C(C=2N=C(N)N=CC=2)=C(C=2C=CC(F)=CC=2)N=C1 RSVKJKGWCXEMRK-UHFFFAOYSA-N 0.000 description 7
• PCRYMXOZDCYMCW-UHFFFAOYSA-N 1-(1,2-oxazol-3-yl)ethyl methanesulfonate Chemical compound CS(=O)(=O)OC(C)C=1C=CON=1 PCRYMXOZDCYMCW-UHFFFAOYSA-N 0.000 description 6
• ICNSLEJMOHSUIQ-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-3-pyrrolidin-3-ylimidazol-4-yl]pyrimidin-2-amine Chemical compound NC1=NC=CC(C=2N(C=NC=2C=2C=CC(F)=CC=2)C2CNCC2)=N1 ICNSLEJMOHSUIQ-UHFFFAOYSA-N 0.000 description 6
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• 235000017557 sodium bicarbonate Nutrition 0.000 description 6
• 239000011780 sodium chloride Substances 0.000 description 6
• BIWYPOOLPBLUDC-UHFFFAOYSA-N tert-butyl 3-[5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)imidazol-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC1N1C(C=2N=C(N)N=CC=2)=C(C=2C=CC(F)=CC=2)N=C1 BIWYPOOLPBLUDC-UHFFFAOYSA-N 0.000 description 6
• UXCQPEDHCCJBNL-UHFFFAOYSA-N 1-[(4-fluorophenyl)-isocyanomethyl]sulfonyl-4-methylbenzene Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C([N+]#[C-])C1=CC=C(F)C=C1 UXCQPEDHCCJBNL-UHFFFAOYSA-N 0.000 description 5
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• ZJMUDVNRVYUARC-UHFFFAOYSA-N 4-(5-phenyl-3-piperidin-4-ylimidazol-4-yl)pyrimidine Chemical compound C1CNCCC1N1C(C=2N=CN=CC=2)=C(C=2C=CC=CC=2)N=C1 ZJMUDVNRVYUARC-UHFFFAOYSA-N 0.000 description 5
• CGBOENVKVOIUDW-UHFFFAOYSA-N 4-[3-(azetidin-3-yl)-5-(4-fluorophenyl)imidazol-4-yl]pyrimidin-2-amine Chemical compound NC1=NC=CC(C=2N(C=NC=2C=2C=CC(F)=CC=2)C2CNC2)=N1 CGBOENVKVOIUDW-UHFFFAOYSA-N 0.000 description 5
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• DFZIBCAWOSFLFR-AATRIKPKSA-N (e)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one Chemical compound COC(OC)C(=O)\C=C\N(C)C DFZIBCAWOSFLFR-AATRIKPKSA-N 0.000 description 4
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